EP2614053B1 - Procédé de production de composés de pyridazinone et des intermédiaires de ceux-ci - Google Patents

Procédé de production de composés de pyridazinone et des intermédiaires de ceux-ci Download PDF

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EP2614053B1
EP2614053B1 EP11823693.4A EP11823693A EP2614053B1 EP 2614053 B1 EP2614053 B1 EP 2614053B1 EP 11823693 A EP11823693 A EP 11823693A EP 2614053 B1 EP2614053 B1 EP 2614053B1
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group
alkyl
halogens
alkoxy
compound
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EP2614053A4 (fr
EP2614053A1 (fr
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Markus Jachmann
Takayuki Wakamatsu
Mitsuharu Anryu
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C243/32—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/76—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/48—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/88—Unsaturated compounds containing keto groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C07D237/16—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/18—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a method for producing pyridazinone compounds and intermediates thereof.
  • a certain pyridazinone compound is known to be useful as an active ingredient in a medicine or pesticide or be used as an intermediate of a medicine or pesticide (see, Patent Literatures 1-10).
  • Patent Literature 11 JP-A-2008-133252
  • Patent Literature 11 discloses a specific pyridazinone compound and a herbizide containing the same.
  • the present invention provides a novel method for producing pyridazinone compounds.
  • the present invention relates to a novel method for producing pyridazinone compounds and the intermediates thereof.
  • the summary is shown below.
  • various pyridazinone compounds which are useful as an active ingredient in a medicine or pesticide can be prepared.
  • the present invention provides the following items 7 to 13, 19 and 48 to 51.
  • the other items are disclosed as reference.
  • C1-C6 alkylthio group optionally substituted with one or more halogens: a methylthio group, a trifluoromethylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, and a hexylthio group; C1-C6 alkylsulfinyl group optionally substituted with one or more halogens: a methylsulfinyl group, a trifluoromethylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group; C1-C6 alkylsulfonyl group optionally substituted with one or more halogens: a methylsulfonyl group, a trifluoromethylsul
  • C3-C6 cycloalkylamino group a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, and a cyclohexylamino group;
  • (C1-C6 alkyl)carbonyl group optionally substituted with one or more halogens: an acetyl group, a trifluoroacetyl group, a propionyl group, a pentafluoropropionyl group, an isobutyryl group, and a trimethylacetyl group;
  • (C3-C6 cycloalkyl)carbonyl group optionally substituted with one or more halogens: a cyclopropylcarbonyl group, a 2-chlorocyclopropylcarbonyl group, a 2-bromocyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, and a cyclohexylcarbonyl group;
  • (C1-C6 alkoxy)carbonyl group optionally substituted with one or more halogens: a methoxycarbonyl group, an ethoxycarbonyl group
  • C6-C10 aryl group optionally having one or more substituents: a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2,3-dimethylphenyl group, a 2,4-dimethylphenyl group, a 3,4-dimethylphenyl group, a 2,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 3,5-dimethylphenyl group, a 2,3,4-trimethylphenyl group, a 2,3,5-trimethylphenyl group, a 2,3,6-trimethylphenyl group, a 2,4,5-trimethylphenyl group, a 2,4,6-trimethylphenyl group, a 3,4,5-trimethylphenyl group, a 2-ethylphenyl group, a 3-ethylphenyl group, a 4-ethylphenyl group, a 2,3-diethylpheny
  • 5- or 6-membered heteroaryl group optionally having one or more substituents: a 1-pyrazolyl group, a 2-pyrazolyl group, a 3-pyrazolyl group, a 5-methyl-1-pyrazolyl group, a 5-ethyl-1-pyrazolyl group, a 3-phenyl-5-methyl-1-pyrazolyl group, a 3-phenyl-5-ethyl-1-pyrazolyl group, a 3-(4-chlorophenyl)-5-methyl-1-pyrazolyl group, a 3-(4-chlorophenyl)-5-ethyl-1-pyrazolyl group, a 3-(4-bromophenyl)-5-methyl-1-pyrazolyl group, a 3-(4-bromophenyl)-5-ethyl-1-pyrazolyl group, a 3-(4-trifluoromethylphenyl)-5-methyl-1-pyrazolyl group, a 3-(4-trifluoromethylphenyl)
  • an indol-1-yl group optionally having one or more substituents: an indol-1-yl group, an indol-2-yl group, an indol-3-yl group, an indol-4-yl group, an indol-5-yl group, an indol-6-yl group, an indol-7-yl group, a 1-methylindol-3-yl group, an indazol-1-yl group, an indazol-3-yl group, an indazol-4-yl group, an indazol-5-yl group, an indazol-6-yl group, an indazol-7-yl group, a benzotriazol-1-yl group, a benzotriazol-4-yl group, a benzotriazol-5-yl group, a benzotriazol-6-yl group, a benzotriazol-7-yl group, a benzofuran-2-yl
  • a compound of the formula (1-a) wherein R1 is a hydrogen atom can exist as tautomers of the formula (1-a') and the formula (1-a").
  • the compound of the formula (1-a) includes all of those tautomers and a mixture of two or more tautomers.
  • R 1 , R 2 , R 3 , R 5 , G, M, n, and V are as defined above.
  • a compound of the formula (1) (hereinafter referred to as Compound (1)) can be prepared by reacting a compound of the formula (2) (hereinafter referred to as Compound (2)) with a compound of the formula (3) (hereinafter referred to as Compound (3)).
  • the reaction is usually performed in the presence of a solvent.
  • a solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as chloroform and dichloromethane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol; an ester solvent such as ethyl acetate; a ketone solvent such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, polyethyleneglycol, tetrahydrofuran, and dioxane; a nitrile solvent such as acetonitrile and propionitrile; an aromatic heterocycle solvent such as pyridine; a sulfoxide solvent such as dimethylsulfoxide
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (2) for an economic reason.
  • the reaction may be performed in the presence of a catalyst.
  • a catalyst include a phase transfer catalyst such as a quaternary ammonium salt such as tetrabutyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium iodide, benzyl tri-n-butylammonium bromide, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, methyl tri-n-butyl ammonium chloride, tetraethyl ammonium chloride, tetra n-butyl ammonium chloride, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium bromide, tetraethyl ammonium iodide, and benzyl trimethyl ammonium iodide; and a quaternary phosphonium salt such as n-heptyl
  • Compound (3) examples include a metal hydroxide such as calcium hydroxide, lithium hydroxide, sodium hydroxide, and potassium hydroxide; a metal alkoxide such as sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, and sodium n-butoxide; and a metal phenoxide such as sodium phenoxide. They may be used as those which are commercially available or timely prepared or diluted with a solvent.
  • the amount of Compound (3) may be one or more moles to 1 mole of Compound (2), though the upper limit is not limited, the amount is usually in the range of 1 to 10 moles.
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 50 °C to boiling point of the used solvent.
  • a reaction mixture may be irradiated with microwave.
  • the reaction time is, though it may be varied depending on the type and amount of Compound (3), the type and amount of solvent, the reaction temperature and the like, usually 0.1 to 100 hours, typically 0.1 to 60 hours.
  • the reaction can be performed by mixing a solution containing Compound (2) with Compound (3) or a solution containing Compound (3).
  • the mixing may be performed by either a method which adds Compound (3) or a solution containing Compound (3) to a solution containing Compound (2), or a method which adds a solution containing Compound (2) to Compound (3) or a solution containing Compound (3), and each of the solvents used in those solutions may be same or different.
  • the catalyst may be added at any stage, and it may be added during the reaction in progress.
  • the reaction mixture thus obtained usually contains Compound (1) as a main product.
  • Compound (1) can be isolated by known procedures such as washing, filtration, concentration, and recrystallization.
  • the isolated Compound (1) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 2 , R 3 , R 5 , G, and n are as defined above.
  • Compound (2) can be prepared by reacting a compound of the formula (4) (hereinafter referred to as Compound (4)) with a base.
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as chloroform and dichloromethane; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; an ester solvent such as ethyl acetate; a ketone solvent such as acetone, methyl ethyl ketone and methyl isobutyl ketone; a nitrile solvent such as acetonitrile and propionitrile; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethyl
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (4) for an economic reason.
  • the reaction may be performed in the presence of a catalyst.
  • a catalyst which can be used are a phase transfer catalyst such as a quaternary ammonium salt such as tetrabutylammonium bromide, tetrabutylammonium iodide, and benzyl tri-n-butylammonium bromide; and a quaternary phosphonium salt such as n-heptyl triphenylphosphonium bromide and tetraphenylphosphonium bromide.
  • the amount of catalyst may be catalytic amount, usually 0.01 to 10 moles to 1 mole of Compound (4).
  • Examples of the base which is used are an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene; a metal amide base such as lithium diisopropylamide and sodium diisopropylamide; a metal disilazide base such as lithium hexamethyldisilazide and potassium hexamethyldisilazide; a metal hydroxide such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; a metal hydride such as sodium hydride and potassium hydride; carbonates such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; phosphates such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; acetates such as sodium acetate; and a metal alkoxide such as sodium methoxide and lithium methoxide;
  • the amount of base may be catalytic amount, usually 0.01 to 10 moles, preferably 0.1 to 5 moles, more preferably 0.1 to 2 moles to 1 mole of Compound (4).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from melting point of the solvent to 70 °C.
  • the reaction time is, though it may be varied depending on the type and amount of base, the type and amount of solvent, the reaction temperature and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction can be performed by mixing a solution containing Compound (4) with a base or a solution containing the base.
  • the mixing may be performed by either a method which adds a base or a solution containing the base to a solution containing Compound (4), or a method which adds a solution containing Compound (4) to a base or a solution containing the base, and each of the solvents used in those solutions may be same or different.
  • a dihydropyridazinone compound of the formula (13) wherein R 2 , R 3 , R 5 , G, and n are as defined above; can be observed.
  • the compound of the formula (13) is a reaction intermediate, and it may be subjected to dehydration after isolation and purification or without isolation.
  • Compound (2) can be isolated by known procedures such as washing, filtration, concentration, and recrystallization.
  • the isolated Compound (2) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • Compound (2) wherein R 3 is not hydrogen can be prepared from a compound wherein R 3 is hydrogen. (see Journal of American Chemical Society, 1945, 67, 60)
  • Compound (2) wherein n is an integer 1 or 2 can be prepared from Compound (2) wherein n is an integer of 0. wherein R 2 , R 3 , R 5 , and G are as defined above.
  • a compound of the formula (2-01) (hereinafter referred to as Compound (2-01)) or a compound of the formula (2-02) (hereinafter referred to as Compound (2-02)) can be prepared by reacting a compound of the formula (2-00) (hereinafter referred to as Compound (2-00)) with an oxidizing agent.
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as chloroform and dichloromethane; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; an ester solvent such as ethyl acetate; a ketone solvent such as acetone, methyl ethyl ketone and methyl isobutyl ketone; a nitrile solvent such as acetonitrile and propionitrile; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; a carboxy
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (2-00) for an economic reason.
  • the reaction may be performed in the presence of a catalyst.
  • a catalyst which can be used are an oxide of heavy metal such as tungsten or vanadium.
  • the amount of catalyst may be catalytic amount, usually 0.01 to 10 moles to 1 mole of Compound (2-O0).
  • oxidizing agent examples include organic peroxide such as tert-butyl hydroperoxide (TBHP); inorganic peroxide such as hydrogen peroxide; and peracid such as meta-chloroperbenzoic acid (mCPBA) and peracetic acid; among of them, a meta-chloroperbenzoic acid and a hydrogen peroxide are preferable.
  • organic peroxide such as tert-butyl hydroperoxide (TBHP)
  • inorganic peroxide such as hydrogen peroxide
  • peracid such as meta-chloroperbenzoic acid (mCPBA) and peracetic acid
  • the amount of oxidizing agent may be, for Compound (2-02) production, two or more moles to 1 mole, preferably 2 to 20 moles, and for Compound (2-O1) production, one or more moles, preferably 1.0 to 1.5 moles to 1 mole of Compound (2-O0).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from melting point of a solvent to 70 °C.
  • the reaction time is, though it may be varied depending on the type and amount of oxidizing agent, the type and amount of solvent, the reaction temperature and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction can be performed by mixing a solution containing Compound (2-O0) with an oxidizing agent or a solution containing the oxidizing agent.
  • the mixing may be performed by either a method which adds an oxidizing agent or a solution containing the oxidizing agent to a solution containing Compound (2-00), or a method which adds a solution containing Compound (2-00) to a oxidizing agent or a solution containing the oxidizing agent, and each of the solvents used in those solutions may be same or different.
  • the catalyst may be added at any stage, and it may be added during the reaction in progress.
  • Compound (2-O1) is a reaction intermediate, and it may be subjected to oxidation after isolation and purification or without isolation.
  • Compound (2-01) or Compound (2-02) can be isolated by known procedures such as washing, filtration, concentration, and recrystallization.
  • the isolated Compound (2-O1) or Compound (2-02) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 2 , R 3 , R 5 , G, n, and X 1 are as defined above.
  • Compound (4) can be prepared by reacting a compound of the formula (6) (hereinafter referred to as Compound (6)) with a compound of the formula (5) (hereinafter referred to as Compound (5)).
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and Xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; an aromatic heterocycle solvent such as pyridine; a hydrocarbon solvent such as hexane and heptane; a nitrile solvent such as acetonitrile and propionitrile; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; an ester solvent such as ethyl acetate; a ketone solvent such as acetone, methyl ethyl ketone and methyl isobutyl ketone; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them,
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (6) for an economic reason.
  • the amount of Compound (5) may usually be one or more moles, preferably 1.0 to 3.0 moles to 1 mole of Compound (6).
  • the reaction may be performed in the presence of a base.
  • Examples of the base which can be used are an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene; a metal amide base such as lithium diisopropylamide and sodium diisopropylamide; a disilazide base such as lithium hexamethyldisilazide and potassium hexamethyldisilazide; a metal hydride such as sodium hydride and potassium hydride; a metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; phosphates such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate; acetates such as sodium acetate; and a metal alkoxide such as sodium methoxide and lithium methoxide; among of them, an organic
  • the amount of the base may usually be one or more moles, preferably 1 to 5 moles to 1 mole of Compound (6).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from -30 °C to 50 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of base, the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction is performed by mixing Compound (6) or a solution containing Compound (6) with a solution containing Compound (5).
  • the mixing may be performed by either a method which adds Compound (6) or a solution containing Compound (6) to a solution containing Compound (5) at a favorable temperature, or a method which adds a solution containing Compound (5) to a solution containing Compound (6) at a favorable temperature, preferably a method which adds a solution containing Compound (6) to a solution containing Compound (5) at a favorable temperature.
  • Each of the solvents used in those solutions may be same or different.
  • a base is used, though the base may be added at any stage, preferably, a base is added to a solution containing Compound (5), and then a solution containing Compound (6) is added at a favorable temperature.
  • the reaction mixture thus obtained usually contains Compound (4) as a main product.
  • Compound (4) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (4) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 2 , R 3 , R 5 , G, and n are as defined above.
  • Compound (4) can be prepared by reacting a compound of the formula (7) (hereinafter referred to as Compound (7)) with a compound of the formula (12) (hereinafter referred to as Compound (12)).
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; a nitrile solvent such as acetonitrile and propionitrile; an ester solvent such as ethyl acetate; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, an alcohol solvent and an aromatic hydrocarbon solvent are preferable
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (12) for an economic reason.
  • Compound (7) can usually be purchased or timely prepared.
  • the method for producing Compound (7) is described, for example, in Organic Synthesis, 1977, 56, 72-74 or Heterocycles, 2007, 73 469-480 .
  • the amount of Compound (7) may usually be one or more moles, preferably 1.0 to 3.0 moles to 1 mole of Compound (12).
  • the reaction may be performed in the presence of a dehydrating agent or an acid.
  • Dehydration may also be achieved by azeotropic distillation.
  • dehydrating agent examples include an inorganic dehydrating agent such as silica gel, molecular sieves, sodium sulfate, and magnesium sulfate.
  • the amount of dehydrating agent may usually be one or more parts by weight, preferably 1 to 5 parts by weight to 1 part by weight of Compound (12).
  • the acid examples include an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, and acetic acid; and an inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid.
  • organic acid such as methanesulfonic acid, p-toluenesulfonic acid, and acetic acid
  • inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid.
  • the amount of acid may usually be catalytic amount, for example, 0.01 to 10 moles to 1 mole of Compound (12).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 0 °C to 150 °C.
  • reaction time is, though it may be varied depending on the reaction temperature, the type and amount of dehydrating agent or acid, the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (4) as a main product.
  • Compound (4) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (4) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 3 , G, and Y are as defined above.
  • Compound (12) can be prepared by reacting a compound of the formula (9) (hereinafter referred to as Compound (9)) with a compound of the formula (14) (hereinafter referred to as Compound (14)).
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; a nitrile solvent such as acetonitrile and propionitrile; an ester solvent such as ethyl acetate; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, an alcohol solvent is preferable.
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (9) for an economic reason.
  • the amount of Compound (14) may usually be one or more moles, preferably 1.0 to 3.0 moles to 1 mole of Compound (9).
  • Compound (14) may be purchased or timely prepared.
  • the method for producing Compound (14) is described, for example, in Science of Synthesis, 40b, 1133-1210.
  • Examples of the compound (14) are hydrazine, monomethylhydrazine, monoethylhydrazine, monomethoxycarbonylhydrazine, monobenzylhydrazine, hydrochloride or sulfate of those hydrazine compounds. Among of them, hydrazine and methylhydrazine are preferable.
  • the reaction may be performed in the presence of a base.
  • Examples of the base which can be used are an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene; a metal amide base such as lithium diisopropylamide and sodium diisopropylamide; a disilazide base such as lithium hexamethyldisilazide and potassium hexamethyldisilazide; a metal hydride such as sodium hydride and potassium hydride; a metal hydroxide such as sodium hydroxide and potassium hydroxide; acetates such as sodium acetate; and a metal alkoxide such as sodium methoxide and lithium methoxide; among of them, an organic base is preferable.
  • an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine
  • the amount of base may usually be catalytic amount, usually 0.1 to 5 moles to 1 mole of Compound (14).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 0 °C to 50 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of base, the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (12), or the salt of Compound (12) when the salt of Compound (14) is used as a main product.
  • a salt of Compound (12) can be converted to Compound (12) by basification with a base such as metal hydroxide (ex. sodium hydroxide, potassium hydroxide) and carbonate (ex. sodium carbonate, sodium hydrogen carbonate and potassium carbonate).
  • Compound (12) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (12) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 2 , R 3 , R 5 , and n are as defined above.
  • Compound (5) can be prepared by reacting a compound of the formula (7) (hereinafter referred to as Compound (7)) with a compound of the formula (14) (hereinafter referred to as Compound (14)).
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene and chlorobenzene, toluene and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; a nitrile solvent such as acetonitrile and propionitrile; an ester solvent such as ethyl acetate; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, an alcohol solvent, an aromatic hydrocarbon solvent, water
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (7) for an economic reason.
  • Compound (14) may be purchased or timely prepared.
  • the method for producing Compound (14) is described, for example, in Science of Synthesis, 40b 1133-1210.
  • Examples of Compound (14) which can be used are hydrazine, monomethylhydrazine, monoethylhydrazine, and monomethoxycarbonylhydrazine, and a hydrate, hydrochloride or sulfate of those hydrazine compounds; among of them, hydrazine, hydrochloride of monobenzylhydrazine and methylhydrazine are preferable.
  • the amount of Compound (14) may usually be one or more moles, preferably 1.0 to 3.0 moles to 1 mole of Compound (7).
  • the reaction may be performed in the presence of a dehydrating agent or an acid.
  • Dehydration may also be achieved by azeotropic distillation.
  • dehydrating agent examples include an inorganic dehydrating agent such as silica gel, molecular sieve, sodium sulfate, and magnesium sulfate.
  • the amount of dehydrating agent may usually be one or more parts by weight, preferably 1 to 5 parts by weight, to 1 part by weight of Compound (7).
  • Examples of the acid which can be used are an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, and acetic acid; and an inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid.
  • an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, and acetic acid
  • an inorganic acid such as hydrochloric acid, sulfuric acid, and phosphoric acid.
  • the amount of acid may usually be catalytic amount, usually 0.01 to 10 moles to 1 mole of Compound (7).
  • Compound (7) may usually be purchased or timely prepared.
  • the method for producing Compound (7) is described, for example, in Organic Synthesis, 1977, 56, 72-74 or Heterocycles, 2007,73 469-480 .
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 0 °C to 50 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of base, the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (5), or salt of Compound (5) when salt of Compound (14) is used as a main product.
  • a salt of Compound (5) can be converted to Compound (5) by basification with a base such as metal hydroxide (ex. sodium hydroxide, potassium hydroxide) and carbonate (ex. sodium carbonate, sodium hydrogen carbonate and potassium carbonate).
  • a base such as metal hydroxide (ex. sodium hydroxide, potassium hydroxide) and carbonate (ex. sodium carbonate, sodium hydrogen carbonate and potassium carbonate).
  • Compound (5) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (5) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • G and X 1 are as defined above.
  • Compound (6) can be prepared by halogenation of a compound of the formula (8) (hereinafter referred to as Compound (8)) with a halogenating agent.
  • a solvent may be used in the reaction.
  • Examples of the solvent which can be used are an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; or a mixture thereof; among of them, an aromatic hydrocarbon solvent is preferable.
  • an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene
  • a halogenated hydrocarbon solvent such as dichloromethane and chloroform
  • a hydrocarbon solvent such as hexane and heptane
  • an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (8) for an economic reason.
  • halogenating agent examples include thionyl chloride, thionyl brominde, phosphorous oxychloride, and oxalyl chloride; among of them, thionyl chloride is preferable.
  • the amount of halogenating agent may be one or more moles to 1 mole of Compound (8). Though the upper limit is not limited, the amount is usually in the range of 1 to 10 moles.
  • the reaction can be performed in the presence of a catalyst.
  • Example of the catalyst which can be used is an amide compound such as dimethylformamide, among of them, dimethylformamide is preferable.
  • the amount of the catalyst may be 0.01 or more moles to 1 mole of Compound (8). Though the upper limit is not limited, the amount is usually in the range of 0.01 to 0.5 moles.
  • the reaction temperature is usually not less than 35 °C and not more than boiling point of the solvent, preferably from 40 °C to 100 °C.
  • reaction time is, though it may be varied depending on the reaction temperature, the type and amount of halogenating agent, the type and amount of solvent, presence or absence of a catalyst and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • reaction mixture thus obtained usually contains Compound (6) as a main product.
  • Compound (6) can be isolated by known procedures such as washing, filtration, concentration, and recrystallization.
  • the isolated Compound (6) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • Compound (6) can be prepared by using Friedel-Crafts acylation as shown in the following scheme: wherein G and X 1 are as defined above. (see European J of Organic Chemistry, 2002, 14, 2298-2307 )
  • Compound (8) can be prepared by hydrolysis of a compound of the formula (9) (hereinafter referred to as Compound (9)).
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol dimethyl ether; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol, tetrahydrofuran, and dioxane; a nitrile solvent such as acetonitrile and propionitrile; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, water, an ether solvent such as tetrahydrofuran , an alcohol solvent such as methanol or an aromatic hydrocarbon solvent such as toluene and xylene;
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (9) for an economic reason.
  • the reaction can be performed in the presence of a base.
  • Examples of the base which can be used are a metal hydroxide such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.
  • the amount of the base may be one or more moles to 1 mole of Compound (9). Though the upper limit is not limited, the amount is usually 1 to 10 moles.
  • the reaction can be performed in the presence of an acid in place of a base.
  • Examples of the acid which can be used are an inorganic acid such as hydrochloric acid, sulfuric acid, acetic acid, and phosphoric acid.
  • the amount of the acid may be a catalytic amount.
  • the upper limit is not limited, the amount is usually in the range of 0.01 to 10 moles to 1 mole of Compound (9).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from room temperature to boiling point of a solvent.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of a base or acid, the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (8) or a salt of Compound (8), when a base was used, as a main product.
  • a salt of Compound (8) can be converted to Compound (8) by acidification with an acid such as hydrochloric acid and sulfuric acid.
  • Compound (8) can be isolated by known procedures such as washing, filtration, concentration, and recrystallization.
  • the isolated Compound (8) can be further purified by conventional techniques such as distillation, recrystallization and column chromatography.
  • Compound (9) can be prepared by reacting a Grignard reagent which is prepared from a compound of the formula (10) (hereinafter referred to as Compound (10)) with a compound of the formula (15) (hereinafter referred to as Compound (15)): wherein Y is as defined above.
  • Compound (10) which can be used are a halogenated benzene such as bromobenzene, chlorobenzene, iodobenzene, 2-methylbromobenzene, 3-methylbromobenzene, 4-methylbromobenzene, 2,4-dimethylbromobenzene, 2,4,6-trimethylbromobenzene, 2,3,5-trimethylbromobenzene, 2,4,6-triethylbromobenzene, 2,4,6-tributylbromobenzene, 2-bromo-4-(4-chlorophenyl)-1-ethylbenzene, and 2,6-diethyl-4-methylbromobenzene; a halogenated naphthalene such as 1-bromonaphthalene and 2-bromonaphthalene; a halogenated furan such as 3-bromofuran; a halogenated pyridine such as 2-bromopyridine, 3-bromobenz
  • the reaction comprises the first step of preparing Grignard reagent from Compound (10) and the second step of reacting Grignard reagent with Compound (15).
  • the reaction is usually performed in the presence of a solvent.
  • Examples of the solvent which can be used are an aromatic hydrocarbon solvent such as benzene toluene, and xylene; a hydrocarbon solvent such as hexane and heptane; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; or a mixture thereof; among of them, an ether solvent is preferable.
  • aromatic hydrocarbon solvent such as benzene toluene, and xylene
  • a hydrocarbon solvent such as hexane and heptane
  • an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane
  • a mixture thereof among of them, an ether solvent is preferable.
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (10) for an economic reason.
  • the type of magnesium used in the present invention is not limited, but cutting chip form is favorable for a safety and availability reason.
  • the amount of magnesium may be one or more moles to 1 mole of Compound (10). Though the upper limit is not limited, the amount is usually in the range of 1 to 2 moles.
  • An activating agent such as dibromoethane and iodine may be added because commercial magnesium has usually oxide layer, thereby the reactivity is reduced.
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 0 °C to 50 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the form and amount of magnesium, the type and amount of solvent, presence or absence of an activating agent ant the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction is usually performed in the presence of a solvent.
  • Examples of the solvent which can be used are an aromatic hydrocarbon solvent such as benzene toluene, and xylene; a hydrocarbon solvent such as hexane and heptane; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; or a mixture thereof; among of them, an ether solvent and an aromatic hydrocarbon solvent; or a mixture thereof are preferable.
  • an aromatic hydrocarbon solvent such as benzene toluene, and xylene
  • a hydrocarbon solvent such as hexane and heptane
  • an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane
  • an ether solvent and an aromatic hydrocarbon solvent or a mixture thereof are preferable.
  • the solvent may be same as or different from the solvent used in the first step.
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (10) for an economic reason.
  • Compound (15) which can be used are oxalates which the number of carbon in the ester moiety is 1-6 such as dimethyl oxalate, diethyl oxalate, dipropyl oxalate, dibutyl oxalate, dipentyl oxalate, and dihexyl oxalate; among of them, a diethyl oxalate is preferable.
  • the amount of Compound (15) may be one or more moles to 1 mole of Compound (10). Though the upper limit is not limited, the amount is usually in the range of 1 to 3 moles.
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 0 °C to 30 °C.
  • reaction time is, though it may be varied depending on the reaction temperature, the type and amount of Compound (15), the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction is performed by mixing a solution from the first step with Compound (15) or a solution of Compound (15).
  • the mixing may be performed by either a method wherein a solution from the first step at a favorable temperature, then a solution containing Compound (15) is added thereto; or a method wherein a solution from the first step is added dropwise to a solution containing Compound (15) at a favorable temperature.
  • the reaction mixture thus obtained usually contains Compound (9) as a main product.
  • Compound (9) can be isolated by known procedures such as washing, filtration, concentration, and recrystallization.
  • the isolated Compound (9) can be further purified by conventional techniques such as distillation, and column chromatography. (see Journal of Organic Chemistry., 1987, 52, 5026-5030 )
  • Compound (9) can be prepared from Compound (16) by reacting a compound which is prepared by metalation reaction using an alkyl lithium base such as n-butyl lithium and tert-butyl lithium or a metal amide base such as lithium diisopropylamide with an oxalate diester as shown in the following scheme: wherein X 3 represents a hydrogen atom, and G and Y are as defined above.
  • R 10 , R 11 and G B are as defined above.
  • a compound of the formula (17) (hereinafter referred to as Compound (17)) can be prepared by reacting a compound of the formula (12B) (hereinafter referred to as Compound (12B)) with a compound of the formula (20) (hereinafter referred to as Compound (20))
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, and ethylene glycol dimethyl ether; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; a nitrile solvent such as acetonitrile and propionitrile; a ester solvent such as ethyl acetate; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, an alcohol solvent and an aromatic hydrocarbon
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (12B) for an economic reason.
  • the compound (20) can be purchased.
  • Examples of the compound (20) are formaldehyde, acetaldehyde, propanal, butanal, isobutanal, benzaldehyde, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetophnone, cyclopentanone, and cyclohexanone.
  • the amount of the compound (20) may be one or more moles, preferably 1.0 to 3.0 moles to 1 mole of Compound (12B).
  • the reaction may be performed in the presence of a dehydrating agent or an acid.
  • Dehydration may also be achieved by azeotropic distillation.
  • dehydrating agent examples include inorganic dehydrating agent such as silica gel, molecular sieves, sodium sulfate and magnesium sulfate.
  • the amount of the dehydrating agent may be one or more parts by weight, preferably 1 to 5 parts by weight to 1 part by weight of Compound (12B).
  • the acid examples include an organic acid such as methanesulfonic acid, p-toluenesulfonic acid and acetic acid, and an inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid.
  • organic acid such as methanesulfonic acid, p-toluenesulfonic acid and acetic acid
  • inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid.
  • the amount of the acid is 0.01 to 10 moles to 1 mole of Compound (12B).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably from 0 °C to 150 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of the dehydrating agent or the acid, the type and amount of solvent and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (12) as a main product.
  • Compound (17) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (17) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 3B , R 10 , R 11 , L and G B are as defined above.
  • a compound of the formula (19) (hereinafter referred to as Compound (19)) can be prepared by reacting Compound (17) with a compound of the formula (18) (hereinafter referred to as Compound (18)).
  • Examples of the compound (18) are methyl iodide, ethyl bromide, benzyl chloride, methyl methanesulfonate dimethylsulfate, and diethylsulfate. They may be purchased or timely prepared.
  • the reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; a nitrile solvent such as acetonitrile and propionitrile; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, and dioxane; an ester solvent such as ethyl acetate; a ketone solvent such as acetone, methyl ethyl ketone and methyl isobutyl ketone; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, a ketone solvent and an aromatic hydro
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (17) for an economic reason.
  • the amount of Compound (18) may usually be one or more moles, preferably 1.0 to 3.0 moles to 1 mole of Compound (17).
  • the reaction may be performed in the presence of a base.
  • Examples of the base which can be used are an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene; a metal hydride such as sodium hydride and potassium hydride; a metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; a carbonate such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; a phosphate such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate; an acetate such as sodium acetate; and a metal alkoxide such as sodium methoxide and lithium methoxide; among of them, a metal hydroxide and a carbonate are preferable.
  • an organic base such as pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, and
  • the amount of base may be one or more moles, usually 1 to 5 moles to 1 mole of Compound (17).
  • the reaction may be performed in the presence of a catalyst.
  • the catalyst examples include a phase transfer catalyst such as a quaternary ammonium salt such as tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and benzyl tri-n-butylammonium bromide, and a quaternary phosphonium salt such as n-heptyltriphenylphosphonium bromide and tetraphenylphosphonium bromide; and a hydrazine such as hydrazine hydrate, methyl hydrazine and N, N-dimethylhydrazine.
  • a phase transfer catalyst such as a quaternary ammonium salt such as tetrabutyl ammonium bromide, tetrabutyl ammonium iodide and benzyl tri-n-butylammonium bromide, and a quaternary phosphonium salt such as n-heptyltriphenylphosphonium bromid
  • the amount of catalyst may be catalytic amount, usually 0.01 to 1 moles to 1 mole of Compound (17).
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably -30 °C to 50 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of base, the type and amount of solvent, and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (19) as a main product.
  • Compound (19) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (19) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 3B , R 10 , R 11 and G B are as defined above.
  • a compound of the formula (12C) (hereinafter referred to as Compound (12C)) can be prepared by decomposing Compound (19).
  • Examples of the method of the decomposition are hydrolysis and hydrogenation.
  • a hydrolysis reaction is usually performed in the presence of a solvent.
  • the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a halogenated hydrocarbon solvent such as dichloromethane and chloroform; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran and dioxane; a nitrile solvent such as acetonitrile and propionitrile; a sulfoxide solvent such as dimethylsulfoxide; an amide solvent such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone; or a mixture thereof; among of them, water, an alcohol solvent, an ether solvent and a mixture thereof are preferable.
  • an aromatic hydrocarbon solvent such as
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (19) for an economic reason.
  • the reaction may be performed in the presence of an acid.
  • the acid examples include an organic acid such as methanesulfonic acid, p-toluenesulfonic acid and acetic acid; and an inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid.
  • organic acid such as methanesulfonic acid, p-toluenesulfonic acid and acetic acid
  • inorganic acid such as hydrochloric acid, sulfuric acid and phosphoric acid.
  • the amount of the acid may be usually a catalytic amount, and 0.01 to 1 mole to 1 mole of Compound (19).
  • This reaction may be performed in the presence of a hydroxylamine; or a hydrochloride, a sulfate or a carbonate thereof.
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably 0 °C to 150 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of acid, the type and amount of solvent, and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (12C) as a main product.
  • Compound (12C) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (12C) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • R 10 and R 11 are a phenyl group
  • a hydrogenation reaction can be performed.
  • a hydrogenation reaction is usually performed in the presence of a solvent.
  • Examples of the solvent which can be used are water; an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene; a hydrocarbon solvent such as hexane and heptane; an alcohol solvent such as methanol, ethanol, isopropanol, n-butanol and ethylene glycol; an ether solvent such as 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran and dioxane; an ester solvent such as ethyl acetate; or a mixture thereof; among of them, water, an alcohol solvent, an ether solvent and a mixture thereof are preferable.
  • an aromatic hydrocarbon solvent such as benzene, chlorobenzene, toluene, and xylene
  • a hydrocarbon solvent such as hexane and heptane
  • an alcohol solvent such as methanol, ethanol, isopropanol, n-butano
  • the amount of solvent is not limited, but usually 100 or less parts by weight to 1 part by weight of Compound (19) for an economic reason.
  • the reaction may be usually performed in the presence of a catalyst.
  • Examples of the catalyst are those which metal such as palladium, platinum and rhodium is supported on activated carbon.
  • the rate of metal to activated carbon is not limited, but usually 0.1 to 10 % by weight to 100 % by weight activated carbon.
  • the amount of catalyst may be catalytic amount, and 0.001 to 0.1 part by weight to 1 part by weight of compound (19).
  • the reaction pressure is usually not less than atmospheric pressure and not more than 10 atm.
  • the reaction temperature is usually not less than melting point of a solvent and not more than boiling point of the solvent, preferably 0 °C to 80 °C.
  • the reaction time is, though it may be varied depending on the reaction temperature, the type and amount of catalyst, the type and amount of solvent, and the like, usually 0.1 to 100 hours, typically 0.1 to 24 hours.
  • the reaction mixture thus obtained usually contains Compound (12C) as a main product.
  • Compound (12C) can be isolated by known procedures such as filtration, concentration, and recrystallization.
  • the isolated Compound (12C) can be further purified by conventional techniques such as distillation, column chromatography, and recrystallization.
  • Examples of the compound which can be prepared by the method for producing of the present invention include as follows.
  • Me means a methyl group
  • Et means an ethyl group
  • n-Pr means a n-propyl group
  • i-Pr means an isopropyl group
  • c-Pr means a cyclopropyl group
  • n-Bu means a n-butyl group
  • Ph means a phenyl group.
  • room temperature means usually 10 to 30 °C.
  • silica gel 60 (spheral, neutral, particle size: 63-210 nm, from KANTO CHEMICAL CO., INC.) was used.
  • a mixed solvent is used as a developing solvent, the mixture ratio by volume of each solvent is shown in parentheses.
  • 1 H NMR means proton nuclear magnetic resonance, and was measured with JEOL AL-400 (400Hz) type and Bruker ADBANCE400 (400Hz) type spectrometer using tetramethylsilan as an internal standard, and chemical shift ( ⁇ ) was shown by ppm.
  • test tube (outside diameter: 21mm ⁇ X overall length: 160mm), 4-(2,6-diethyl-4-methylphenyl)- 2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (52.2 mg), ethanol (674.3 mg), and sodium ethoxide (121.8 mg) were added under a nitrogen atmosphere at room temperature and stirred for 4 hours at 70 °C. To the reaction mixture was added water (4 ml) at room temperature, and extracted with tert-butyl methyl ether.
  • ethyl 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetate (9-a) (320.82 g) and tetrahydrofuran (600 ml) were added at room temperature and cooled. 10.7% by weight of aqueous sodium hydroxide solution (900 ml) was added dropwise at 10 °C over 2 hours. The resulting mixture was stirred at room temperature for 1 hour. After the organic solvent was removed under reduced pressure, tert-butyl methyl ether was added to the aqueous layer to wash.
  • test tube (outside diameter: 21mm ⁇ X overall length: 160mm), 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39) (104.0 mg), potassium carbonate (60.2 mg) and dimethylformamide (300 mg) were added at room temperature.
  • test tube (outside diameter: 21mm ⁇ X overall length: 160mm), 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39) (201.0 mg), potassium carbonate (115.1 mg), and methanol (757 ⁇ l) were added under ice-cooling.
  • reaction mixture was stirred for 2 hours, and added additional potassium t-butoxide (0.166 g). Then, the resulting mixture was stirred for 2 hours. The reaction mixture was poured into water (70 ml), and extracted with ethyl acetate (50 ml) 2 times.
  • reaction mixture was stirred for 30 minutes, and then potassium t-butoxide (0.67 g) was added.
  • the resulting reaction mixture was stirred for 30 minutes, poured into water (70 ml), and extracted with ethyl acetate (100 ml) 2 times.
  • reaction mixture was poured into water (30 ml), added sodium sulfite (0.4 g), and extracted with t-butyl methyl ether (30 ml) 4 times.
  • magnesium (cutting chip) (51.4 g) and tetrahydrofuran (anhydrous) (250 ml) were added under a nitrogen atmosphere. After the temperature of the mixture was raised to about 30 °C, dibromoethane, (17.3 g) was added dropwise. The resulting mixture was stirred for 30 minutes.
  • 1,3,5-triethylbromobenzene (10-b) (443.5 g) dissolved in tetrahydrofuran (250 ml) was added dropwise over 2 hours. The mixture was stirred at 50 °C for 1 hour, and cooled to room temperature to give a solution of 1,3,5-triethylphenylmagnesium bromide in tetrahydrofuran.
  • diethyl oxalate 295 g
  • tetrahydrofuran anhydrous
  • the above mentioned solution of 1,3,5-triethylphenylmagnesium bromide in tetrahydrofuran was added thereto with keeping the temperature below 10 °C.
  • the resulting mixture was stirred at room temperature for 2 hours.
  • the pH of the mixture was adjusted to less than 2 with 20 w/w % of sulfuric acid under ice-cooling.
  • the mixture was extracted with toluene.
  • 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (116.0 g), tetrahydrofuran (anhydrous) (600 ml), and triethylamine (98.5 ml) were added under a nitrogen atmosphere, and cooled to about 1 °C.
  • 2-(1,3,5-triethylphenyl)-2-oxoacetyl chloride (6-b) (178.5 g) was added dropwise, and stirred at 0 °C for 1 hour.
  • the reaction mixture was added dropwise to hexane (3 L) at room temperature, and stirred for 1 hour.
  • reaction mixture was added to water, and extracted with toluene 3 times.
  • the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After the insolubles were removed by filtration, the filtrate was concentrated under reduced pressure.
  • reaction mixture was added to iced water, and the precipitated solids were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 3.4 g of 1-methyl-1-[2(1-methyl-1H-indol-3-yl)-2-oxoacetyl]-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-203-(13)28).
  • diethyl oxalate 39.4 g
  • tetrahydrofuran anhydrous 66.3 g
  • diethyl oxalate 39.4 g
  • tetrahydrofuran anhydrous 66.3 g
  • diethylether solution dropwise at less than -65 °C, and stirred for 5 hours.
  • water was added at less than -40 °C, and extracted with methyl t-butyl ether 3 times. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • magnesium (cutting chip) (66.2 g), tetrahydrofuran (anhydrous) (494 g), and toluene (549 g) were added under a nitrogen atmosphere at room temperature.
  • dibromoethane 26.9 g was added dropwise over 10 minutes at about 20 °C, and then the internal temperature was raised to 33 °C.
  • the resulting mixture was stirred at 30 °C for 20 minutes.
  • 2,6-diethyl-4-methylbromobenzene (10-a) (549.0 g) was added dropwise thereto at 40 °C over 1 hour.
  • sodium p-toluenesulfinate (20-a) (9.25 g), tetrabutylammonium bromide (1.65 g), toluene (29 g), and chloroacetone (21-a) (5.0 g) were added, and stirred at 65 °C for 1.25 hours.
  • water (10 g) was added, and stirred for 4 hours.
  • the organic layer was separated, and the aqueous layer was extracted with toluene 2 times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • test-tube (outside diameter: 21 mm ⁇ x overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfanyl-2,3-dihydro-3-pyridazinone ((2-4)-(1)-39) (300 mg), N-methyl-2-pyrrolidone (875 mg), and sodium methoxide (410 mg) were added, and stirred at 90 °C for 16 hours. After the mixture was cooled to room temperature, water was added and washed with toluene. To the aqueous layer, 10 w/w % of hydrochloric acid was added to adjust pH to 1, and extracted with toluene 3 times.
  • magnesium (cutting chip) (296 mg) and anhydrous tetrahydrofuran (6.75 ml) were added under a nitrogen atmosphere.
  • Dibromoethane (95 mg) was added dropwise, and stirred at 50 °C for 30 minutes.
  • diethyl oxalate (1.78 g) and tetrahydrofuran (anhydrous) (6.75 ml) were added under a nitrogen atmosphere
  • diethyl oxalate (1.78 g) was added dropwise, and stirred at room temperature for 30 minutes.
  • the pH of the mixture was adjusted to less than 2 with hydrochloric acid (10 w/w %) under ice-cooling, and the mixture was extracted with toluene 3 times.
  • 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine(5-2-1) (670 mg), tetrahydrofuran (anhydrous) (2.25 ml), and triethylamine (390 mg) were added under a nitrogen atmosphere.
  • 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl chloride (6-c) (937 mg) was added dropwise at 0 °C and stirred for 2 hours.
  • test tube (outside diameter 21 mm ⁇ x overall length 160mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5), 0.5 ml of methanol, 10 mg of 10 wt% Pd-c and one drop of concentrated hydrochloric acid were added and the mixture was stirred at 0 °C for 7 hours under hydrogen atmosphere. An unsolved substance was removed by filtration and washed with methanol.
  • test tube (outside diameter 21 mm ⁇ x overall length 160mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380mg of methanol and 58 ⁇ l of propanal were added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times.
  • test tube (outside diameter 21 mm ⁇ x overall length 160 mm)
  • 380 mg of methanol and 45 ⁇ l of acetaldehyde were added and the mixture was stirred at room temperature for 2 hours.
  • test tube (outside diameter 21 mm ⁇ x overall length 160 mm)
  • 380 mg of methanol and 130 ⁇ l of 37 wt% formalin aqueous solution were added and the mixture was stirred at room temperature for 2.5 hours.

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Claims (12)

  1. Procédé de production d'un composé de formule (1) :
    Figure imgb0287
     qui comprend les étapes consistant à :
    faire réagir un composé de formule (4) :
    Figure imgb0288
    avec une base pour obtenir un composé de formule (2) :
    Figure imgb0289
     et
    faire réagir le composé de formule (2) avec un composé de formule (3) :

            M(OR1)v     (3) ;

    les symboles dans les formules (1), (2), (3) et (4) étant tels que définis ci-dessous :
    R1 représente un atome d'hydrogène, un groupe alkyle en C1-C6 ou un groupe phényle ;
    le groupe alkyle en C1-C6 pouvant être éventuellement substitué par un ou plusieurs atomes d'halogène, à condition que, s'il est substitué par deux atomes d'halogène ou plus, les halogènes puissent être identiques ou différents ; et
    le groupe phényle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe 1, à condition que, s'ils ont deux substituants ou plus, alors les substituants puissent être identiques ou différents ;
    le groupe 1 est constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, et un groupe (alcoxy en C1-C6)alkyle en C1-C6 ;
    dans le groupe 1, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, et le groupe (alcoxy en C1-C6) alkyle en C1-C6 peuvent être éventuellement substitués par un ou plusieurs atomes d'halogènes, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, alors les atomes d'halogènes puissent être identiques ou différents ;
    R2 représente un atome d'hydrogène, un groupe alkyle en C1-C6, un groupe (alcoxy en C1-C6) alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe (alkylthio en C1-C6) alkyle en C1-C6, un groupe (alkylsulfinyle en C1-C6) alkyle C1-C6, un groupe (alkylsulfonyle en C1-C6) alkyle C1-C6, un groupe phényle, ou un groupe hétéroaryle de 5 ou 6 membres ;
    le groupe alkyle en C1-C6, le groupe (alcoxy en C1-C6) alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe (alkylthio en C1-C6)alkyle en C1-C6, le groupe (alkylsulfinyle en C1-C6) alkyle C1-C6, et le groupe (alkylsulfonyle en C1-C6)alkyle en C1-C6 pouvant être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, alors les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle et le groupe hétéroaryle de 5 ou 6 membres pouvant éventuellement avoir un ou plusieurs substituants choisis dans le groupe 2, à condition que, s'ils ont deux substituants ou plus, alors les substituants puissent être identiques ou différents ;
    le groupe 2 étant constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe formyle, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, un groupe (alcoxy en C1-C6) alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe alkylthio en C1-C6, un groupe alkylsulfinyle en C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe alkylamino en C1-C6, un groupe di(alkyle en C1-C6)amino, un groupe cycloalkylamino en C3-C6, un groupe (alkyle en C1-C6) carbonyle, un groupe (cycloalkyle en C3-C6)carbonyle, un groupe (alcoxy en C1-C6)carbonyle, un groupe (alkylamino en C1-C6) carbonyle, un groupe di(alkyle en C1-C6)aminocarbonyle, un groupe (cycloalkylamino en C3-C6)carbonyle, et un groupe tri(alkyle en C1-C6) silyle ;
    dans le groupe 2, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, le groupe (alcoxy en C1-C6) alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe alkylthio en C1-C6, le groupe alkylsulfinyle en C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6)carbonyle, le groupe (cycloalkyle en C3-C6)carbonyle et le groupe (alcoxy en C1-C6) carbonyle peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que s'ils sont substitués par un ou plusieurs atomes d'halogène, les atomes d'halogène puissent être identiques ou différents,
    R3 représente un atome d'hydrogène, un groupe alkyle en C1-C6, un groupe (alcoxy en C1-C6)alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe (alkylthio en C1-C6)alkyle en C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe (alkyle en C1-C6) carbonyle, un groupe (alcoxy en C1-C6) carbonyle, un groupe (alkylamino en C1-C6)carbonyle, un groupe di(alkyle en C1-C6)aminocarbonyle, un groupe (cycloalkylamino en C3-C6)carbonyle, un groupe phényle, un groupe benzyle, ou un groupe phénylsulfonyle ;
    le groupe alkyle en C1-C6, le groupe (alcoxy en C1-C6) alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe (alkylthio en C1-C6)alkyle en C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6) carbonyle et le groupe (alcoxy en C1-C6)carbonyle pouvant être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle, le groupe benzyle, et le groupe phénylsulfonyle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe 3 à condition que, s'ils ont deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 3 est constitué par un atome d'halogène, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6 et un groupe (alcoxy en C1-C6)alkyle en C1-C6 ;
    dans le groupe 3, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6 et le groupe (alcoxy en C1-C6)alkyle en C1-C6 peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ;
    R5 représente un groupe alkyle en C1-C6 ou un groupe phényle ;
    le groupe alkyle en C1-C6 pouvant être éventuellement substitué par un ou plusieurs atomes d'halogène, à condition que, s'il est substitué par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe 5, à condition que, s'il a deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 5 est constitué par un atome d'halogène, un groupe alkyle en C1-C6 et un groupe alcoxy en C1-C6 ;
    dans le groupe 5, le groupe alkyle en C1-C6 et le groupe alcoxy en C1-C6 peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ;
    G représente un groupe aryle en C6-C10, un groupe hétéroaryle de 5 ou 6 membres, ou un groupe hétéroaryle condensé de 8 à 10 membres ;
    le groupe aryle en C6-C10, le groupe hétéroaryle de 5 ou 6 membres, et le groupe hétéroaryle condensé de 8 à 10 membres pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe R4, à condition que, s'ils ont deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe R4 est constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe formyle, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, un groupe (alcoxy en C1-C6)alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe alkylthio en C1-C6, un groupe alkylsulfinyle en C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe alkylamino en C1-C6, un groupe di(alkyle en C1-C6)amino, un groupe cycloalkylamino en C3-C6, un groupe (alkyle en C1-C6)carbonyle, un groupe (cycloalkyle en C3-C6) carbonyle, un groupe (alcoxy en C1-C6)carbonyle, un groupe (alkylamino en C1-C6)carbonyle, un groupe di(alkyle en C1-C6)aminocarbonyle, un groupe (cycloalkylamino en C3-C6)carbonyle, un groupe tri(alkyle en C1-C6)silyle, un groupe aryle en C6-C10 et un groupe hétéroaryle de 5 ou 6 membres ;
    dans le groupe R4, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, le groupe (alcoxy en C1-C6) alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe alkylthio en C1-C6, le groupe alkylsulfinyle en C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6)carbonyle, le groupe (cycloalkyle en C3-C6)carbonyle et le groupe (alcoxy en C1-C6) carbonyle peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe aryle en C6-C10 et le groupe hétéroaryle de 5 ou 6 membres peut avoir éventuellement un ou plusieurs substituants choisis dans le groupe 4, à condition que, s'ils ont deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 4 est constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe formyle, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, un groupe (alcoxy en C1-C6)alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe alkylthio en C1-C6, un groupe alkylsulfinyle en C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe alkylamino en C1-C6, un groupe di(alkyle en C1-C6)amino, un groupe cycloalkylamino en C3-C6, un groupe (alkyle en C1-C6) carbonyle, un groupe (cycloalkyle en C3-C6) carbonyle, un groupe (alcoxy en C1-C6)carbonyle, un groupe (alkylamino en C1-C6)carbonyle, un groupe di(alkyle en C1-C6)aminocarbonyle, un groupe (cycloalkylamino en C3-C6)carbonyle, et un groupe tri(alkyle en C1-C6)silyle ;
    dans le groupe 4, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, le groupe (alcoxy en C1-C6) alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe alkylthio en C1-C6, le groupe alkylsulfinyle en C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6) carbonyle, le groupe (cycloalkyle en C3-C6) carbonyle et le groupe (alcoxy en C1-C6) carbonyle peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ;
    n représente un entier égal à 0, 1 ou 2 ;
    V représente un entier égal à 1 ou 2 ; et
    M représente un métal alcalin quand V est un entier égal à 1, et M représente un métal alcalino-terreux quand V est un entier égal à 2.
  2. Procédé de production d'un composé de formule (2) :
    Figure imgb0290
     qui consiste à faire réagir un composé de formule (4) :
    Figure imgb0291
     avec une base ;
    les symboles R2, R3, R5, G et n dans les formules (2) et (4) étant tels que définis dans la revendication 1.
  3. Procédé selon la revendication 2, dans lequel G est un groupe phényle, le groupe phényle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe R4, à condition que, s'il a deux substituants ou plus, les substituants puissent être identiques ou différents.
  4. Procédé selon la revendication 2 ou la revendication 3, dans lequel le groupe R4 est le groupe R4-3 ;
    le groupe R4-3 étant constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, un groupe cycloalkyle en C3-C6, un groupe alcynyle en C2-C6, et un groupe phényle ;
    dans le groupe R4-3, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, le groupe cycloalkyle en C3-C6 et le groupe alcynyle en C2-C6 peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle peut avoir éventuellement un ou plusieurs substituants choisis dans le groupe 4-3, à condition que, s'il a deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 4-3 est constitué par un atome d'halogène, et un groupe alkyle en C1-C6 ;
    dans le groupe 4-3, le groupe alkyle en C1-C6 peut être éventuellement substitué par un ou plusieurs atomes d'halogène, à condition que, s'il est substitué par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents.
  5. Procédé selon la revendication 4, dans lequel R2 est un atome d'hydrogène, un groupe alkyle en C1-C6 ou un groupe phényle, le groupe alkyle en C1-C6 pouvant être éventuellement substitué par un ou plusieurs atomes d'halogène, à condition que, s'il est substitué par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle pouvant avoir éventuellement un ou plusieurs atomes d'halogène, à condition que, s'il a deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ;
    R3 est un atome d'hydrogène, un groupe alkyle en C1-C6, un groupe (alcoxy en C1-C6)alkyle en C1-C6 ou un groupe benzyle, le groupe alkyle en C1-C6 et le groupe (alcoxy en C1-C6)alkyle en C1-C6 pouvant être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe benzyle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe constitué par un atome d'halogène, un groupe alkyle en C1-C6, et un groupe alcoxy en C1-C6, à condition que, s'il possède deux substituants ou plus, les substituants puissent être identiques ou différents ;
    R5 est un groupe alkyle en C1-C6 ou un groupe phényle, le groupe alkyle en C1-C6 pouvant être éventuellement substitué par un ou plusieurs atomes d'halogène, à condition que, s'il est substitué par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle pouvant avoir éventuellement un groupe alkyle en C1-C6, à condition que, s'il possède deux groupes alkyle en C1-C6 ou plus, les groupes alkyle en C1-C6 puissent être identiques ou différents ; et
    G est un groupe phényle, un groupe pyridyle, un groupe indolyle ou un groupe pyrazolyle, le groupe phényle, le groupe pyridyle, le groupe indolyle et le groupe pyrazolyle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe R4-3, à condition que, s'ils ont deux substituants ou plus, les substituants puissent être identiques ou différents.
  6. Procédé selon la revendication 2, dans lequel R2 est un groupe méthyle, un groupe 4-fluorophényle ou un groupe trifluorométhyle, R3 est un groupe méthyle ou un groupe benzyle, R5 est un groupe méthyle ou un groupe 4-méthylphényle et G est un groupe 2,4,6-triéthylphényle, un groupe 2-éthyl-5-(4-chlorophényl)phényle, un groupe 1-méthylindol-3-yle ou un groupe 2,6-diéthyl-4-méthylphényle.
  7. Procédé de production d'un composé de formule (1) :
    Figure imgb0292
     qui comprend les étapes consistant à :
    faire réagir un composé de formule (5) :
    Figure imgb0293
    avec un composé de formule (6) :
    Figure imgb0294
    pour obtenir un composé de formule (4) :
    Figure imgb0295
    faire réagir le composé de formule (4) avec une base pour obtenir un composé de formule (2) :
    Figure imgb0296
     et
    faire réagir le composé de formule (2) avec un composé de formule (3) :

            M(OR1)v     (3) ;

    les symboles R1, R2, R3, R5, G, n, V et M dans les formules (1), (2), (3), (4), (5) et (6) étant tels que définis dans la revendication 1 ; et
    X1 représente un atome de fluor, de chlore, de brome ou d'iode.
  8. Procédé de production d'un composé de formule (1) :
    Figure imgb0297
     qui comprend les étapes consistant à :
    faire réagir un composé de formule (7) :
    Figure imgb0298
    avec un composé de formule (12) :
    Figure imgb0299
    pour obtenir un composé de formule (4) :
    Figure imgb0300
    faire réagir le composé de formule (4) avec une base pour obtenir un composé de formule (2) :
    Figure imgb0301
     et
    faire réagir le composé de formule (2) avec un composé de formule (3) :

            M(OR1)v     (3) ;

    les symboles R1, R2, R3, R5, G, n, V et M dans les formules (1), (2), (3), (4), (7) et (12) étant tels que définis dans la revendication 1.
  9. Procédé selon la revendication 1, dans lequel R1 est un atome d'hydrogène, un groupe méthyle, un groupe éthyle, un groupe n-butyle ou un groupe phényle, R2 est un groupe méthyle, un groupe 4-fluorophényle ou un groupe trifluorométhyle, R3 est un groupe méthyle ou un groupe benzyle, R5 est un groupe méthyle ou un groupe 4-méthylphényle et G est un groupe 2,4,6-triéthylphényle, un groupe 2-éthyl-5-(4-chlorophényl)phényle, un groupe 1-méthylindol-3-yle ou un groupe 2,6-diéthyl-4-méthylphényle.
  10. Procédé selon la revendication 7, dans lequel R1 est un atome d'hydrogène, un groupe méthyle, un groupe éthyle, un groupe n-butyle ou un groupe phényle, R2 est un groupe méthyle ou un groupe 4-fluorophényle, R3 est un groupe méthyle ou un groupe benzyle, R5 est un groupe méthyle ou un groupe 4-méthylphényle et G est un groupe 2,4,6-triéthylphényle, un groupe 2-éthyl-5-(4-chlorophényl)phényle, un groupe 1-méthylindol-3-yle ou un groupe 2,6-diéthyl-4-méthylphényle.
  11. Procédé selon la revendication 8, dans lequel R1 est un atome d'hydrogène, un groupe méthyle, un groupe éthyle, un groupe n-butyle ou un groupe phényle, R2 est un groupe méthyle ou un groupe trifluorométhyle, R3 est un groupe méthyle ou un groupe benzyle, R5 est un groupe méthyle ou un groupe 4-méthylphényle et G est un groupe 2,4,6-triéthylphényle, ou un groupe 2,6-diéthyl-4-méthylphényle.
  12. Procédé de production d'un composé de formule (1B) :
    Figure imgb0302
     qui comprend les étapes consistant à :
    faire réagir un composé de formule (12B) :
    Figure imgb0303
    avec un composé de formule (20) :
    Figure imgb0304
    pour obtenir un composé de formule (17) :
    Figure imgb0305
    faire réagir le composé de formule (17) avec un composé de formule (18) :

            L-R3B     (18)

    pour obtenir un composé de formule (19) :
    Figure imgb0306
    décomposer le composé de formule (19) pour obtenir un composé de formule (12C) :
    Figure imgb0307
    faire réagir le composé de formule (12C) avec un composé de formule (7) :
    Figure imgb0308
    pour obtenir un composé de formule (4B) :
    Figure imgb0309
    faire réagir le composé de formule (4B) avec une base pour obtenir un composé de formule (2B) :
    Figure imgb0310
     et
    faire réagir le composé de formule (2B) avec un composé de formule (3) :

            M(OR1)v     (3) ;

    les symboles R1, R2, R5, n, V et M dans les formules (1B), (2B), (3), (4B), (7), (12B), (12C), (16), (17), (18) et (19) étant tels que définis dans la revendication 1 et les autres symboles étant tels que définis ci-dessous :
    R3B représente un groupe alkyle en C1-C6, un groupe (alcoxy en C1-C6)alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe (alkylthio en C1-C6)alkyle C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe (alkyle en C1-C6) carbonyle, un groupe (alcoxy en C1-C6) carbonyle, un groupe di (alkyle en C1-C6)aminocarbonyle, un groupe benzyle, ou un groupe phénylsulfonyle ;
    le groupe alkyle en C1-C6, le groupe (alcoxy en C1-C6)alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe (alkylthio en C1-C6)alkyle C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6)carbonyle et le groupe (alcoxy en C1-C6)carbonyle pouvant être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe benzyle et le groupe phénylsulfonyle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe 3B à condition que, s'ils ont deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 3B est constitué par un atome d'halogène, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6 et un groupe (alcoxy en C1-C6) alkyle en C1-C6 ;
    dans le groupe 3B, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6 et le groupe (alcoxy en C1-C6)alkyle en C1-C6 peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ;
    GB représente un groupe phényle ;
    le groupe phényle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe R4-B, à condition que, s'il a deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe R4-B étant constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe formyle, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, un groupe (alcoxy en C1-C6)alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe alkylthio en C1-C6, un groupe alkylsulfinyle en C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe alkylamino C1-C6, un groupe di(alkyle en C1-C6)amino, un groupe cycloalkylamino en C3-C6, un groupe (alkyle en C1-C6)carbonyle, un groupe (cycloalkyle en C3-C6)carbonyle, un groupe (alcoxy en C1-C6) carbonyle, un groupe (alkylamino en C1-C6)carbonyle, un groupe di(alkyle en C1-C6)aminocarbonyle, un groupe (cycloalkylamino en C3-C6)carbonyle, un groupe tri(alkyle en C1-C6)silyle, un groupe aryle en C6-C10, et un groupe hétéroaryle en 5 ou 6 membres ;
    dans le groupe R4-B, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, le groupe (alcoxy en C1-C6) alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe alkylthio en C1-C6, le groupe alkylsulfinyle en C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6)carbonyle, le groupe (cycloalkyle en C3-C6) carbonyle et le groupe (alcoxy en C1-C6) carbonyle peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe aryle en C6-C10 et le groupe hétéroaryle de 5 ou 6 membres peuvent avoir éventuellement un ou plusieurs substituants choisis dans le groupe 4-B, à condition que, s'ils ont deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 4-B est constitué par un atome d'halogène, un groupe cyano, un groupe nitro, un groupe formyle, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6, un groupe (alcoxy en C1-C6) alkyle en C1-C6, un groupe alcényle en C2-C6, un groupe alcynyle en C2-C6, un groupe cycloalkyle en C3-C6, un groupe alkylthio en C1-C6, un groupe alkylsulfinyle en C1-C6, un groupe alkylsulfonyle en C1-C6, un groupe alkylamino en C1-C6, un groupe di(alkyle en C1-C6)amino, un groupe cycloalkylamino en C3-C6, un groupe (alkyle en C1-C6)carbonyle, un groupe (cycloalkyle en C3-C6) carbonyle, un groupe (alcoxy en C1-C6)carbonyle, un groupe (alkylamino en C1-C6)carbonyle, un groupe di(alkyle en C1-C6)aminocarbonyle, un groupe (cycloalkylamino en C3-C6)carbonyle, et un groupe tri(alkyle en C1-C6)silyle ;
    dans le groupe 4-B, le groupe alkyle en C1-C6, le groupe alcoxy en C1-C6, le groupe (alcoxy en C1-C6)alkyle en C1-C6, le groupe alcényle en C2-C6, le groupe alcynyle en C2-C6, le groupe cycloalkyle en C3-C6, le groupe alkylthio en C1-C6, le groupe alkylsulfinyle en C1-C6, le groupe alkylsulfonyle en C1-C6, le groupe (alkyle en C1-C6) carbonyle, le groupe (cycloalkyle en C3-C6)carbonyle et le groupe (alcoxy en C1-C6) carbonyle peuvent être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que, s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ;
    R10 et R11 peuvent être identiques ou différents et chacun représente un atome d'hydrogène, un groupe alkyle en C1-C6, un groupe cycloalkyle en C3-C6, ou un groupe phényle, ou R10 et R11 peuvent être combinés pour former un groupe cyclique de 5 ou 6 membres avec un atome de carbone qui est lié à R10 et R11,
    le groupe alkyle en C1-C6 et le groupe cycloalkyle en C3-C6 pouvant être éventuellement substitués par un ou plusieurs atomes d'halogène, à condition que s'ils sont substitués par deux atomes d'halogène ou plus, les atomes d'halogène puissent être identiques ou différents ; et le groupe phényle pouvant avoir éventuellement un ou plusieurs substituants choisis dans le groupe 10, à condition que, s'il possède deux substituants ou plus, les substituants puissent être identiques ou différents ;
    le groupe 10 étant constitué par un atome d'halogène, un groupe alkyle en C1-C6 et un groupe alcoxy en C1-C6 ; et
    L représente un atome d'halogène, un groupe alkylsulfonyloxy en C1-C6 ou un groupe alcoxysulfonyloxy en C1-C6.
EP11823693.4A 2010-09-08 2011-09-07 Procédé de production de composés de pyridazinone et des intermédiaires de ceux-ci Not-in-force EP2614053B1 (fr)

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TWI507381B (zh) 2015-11-11
WO2012033225A1 (fr) 2012-03-15
CN104277004A (zh) 2015-01-14
IL232682A (en) 2016-09-29
JP2013028582A (ja) 2013-02-07
AR082912A1 (es) 2013-01-16
US9040709B2 (en) 2015-05-26
KR101851418B1 (ko) 2018-04-23
US8884010B2 (en) 2014-11-11
AU2011299811B2 (en) 2016-03-03
CN104277004B (zh) 2016-08-24
US20130172556A1 (en) 2013-07-04
BR112013005689A2 (pt) 2016-05-03
EP3045450A1 (fr) 2016-07-20
US20140378688A1 (en) 2014-12-25
TW201238939A (en) 2012-10-01
AU2011299811A1 (en) 2013-03-14
CN104326952B (zh) 2016-08-24
CN103180300A (zh) 2013-06-26
IL232681A0 (en) 2014-07-31
CN103180300B (zh) 2015-10-07
IL225121A (en) 2016-09-29
IL232682A0 (en) 2014-07-31
CN104326952A (zh) 2015-02-04
KR20140000678A (ko) 2014-01-03
TWI526421B (zh) 2016-03-21
IL232681A (en) 2017-02-28
EP3045450B1 (fr) 2018-02-07
EP2614053A4 (fr) 2014-03-26
EP2614053A1 (fr) 2013-07-17
TW201531452A (zh) 2015-08-16
KR101851518B1 (ko) 2018-04-23
KR20180003637A (ko) 2018-01-09
JP5790348B2 (ja) 2015-10-07

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